Once a killer, always a killer: from cytotoxic T cell to memory cell.

Abstract

The control of the differentiation pathways followed by responding CD8(+) T cells to produce protective memory cells has been intensely studied. Recent developments have identified heterogeneity at the effector cytotoxic T-lymphocyte level within which a bona fide memory cell precursor has emerged. The challenge now is to identify the cellular and molecular factors that control this developmental pathway. This review considers aspects of the regulation of the induction of effectors, the transition of effectors to memory cells, and the dynamics of the memory population.

Early activation of the naive CD8+ T-cell population results in the generation of the early effector cell (EEC) population, which begins differentiation into short-lived effector cells (SLEC) and memory precursor effector cells (MPECs). These early differentiation events (i.e., the first 3–4 days) correspond to times when high levels of interleukin (IL)-12, IL-15, and interferon-α/-β are found. The next cytokine that appears to work on the responding CD8+ T-cell population is IL-2, as the high-affinity IL-2 receptor is only expressed transiently during this time period (i.e., days 3–5). IL-2 not only works to amplify the whole CD8+ T-cell population but also enhances the differentiation of the EEC population to SLECs. Around the peak of the CD8+ T-cell response, high levels of transforming growth factor (TGF)-β can be found. TGFβ will oppose the actions of homeostatic levels of IL-15 and promote the preferential apoptosis of the EEC and SLEC populations leaving only the MPEC population. The levels of IL-15 in the tissues will also regulate this process as SLECs are exquisitely dependent on IL-15 for their survival, whereas the MPEC population is more dependent on IL-15 for long-term homeostatic proliferation and is dependent on IL-7 for survival.

Model for the role of interleukin (IL)-2 production from ‘helper’ CD4+ T cells in effector CD8+ T-cell differentiation and expansion

Activation of both CD4+ and CD8+ T cells by dendritic cells will occur simultaneously in lymphoid organs. For both CD4+ and CD8+ T cells, activation and subsequent proliferation is mediated by T-cell receptor:pMHC (peptide: major histocompatibility complex) interactions and costimulatory molecules, such as CD28:CD80/86. When the ‘helper’ CD4+ T-cell population reaches a critical mass enough paracrine IL-2 will be produced to ‘help’ maintain the expansion and differentiation of CD8+ T-cell responders. IL-2 will act on the CD25+ early effector cells (EECs) population and further upregulate the expression of CD25, at which time it will help direct the differentiation of the EEC. IL-2 will promote the preferential differentiation toward short-lived effector cells, but is likely important in the expansion of all effector cells.